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Variants in ACAD10 are associated with type 2 diabetes, insulin resistance and lipid oxidation in Pima Indians.

ABSTRACT: AIMS/HYPOTHESIS:A prior genome-wide association study in Pima Indians identified a variant within the ACAD10 gene that is associated with early-onset type 2 diabetes. Acylcoenzyme A dehydrogenase 10 (ACAD10) catalyses mitochondrial fatty acid beta-oxidation, which plays a pivotal role in developing insulin resistance and type 2 diabetes. Therefore, ACAD10 was analysed as a positional and biological candidate for type 2 diabetes. METHODS:Twenty-three SNPs were genotyped in 1,500 Pima Indians to determine the linkage disequilibrium pattern across ACAD10. Association with type 2 diabetes was determined by genotyping four tag single nucleotide polymorphisms (SNPs) in a population-based sample of 3,501 full-heritage Pima Indians; two associated SNPs were further genotyped in a second population-based sample of 3,723 American Indians. Associations with quantitative traits were assessed in 415 non-diabetic full heritage Pima individuals who had been metabolically phenotyped. RESULTS:SNPs rs601663 and rs659964 were associated with type 2 diabetes in the full-heritage Pima Indian sample (p=0.04 and 0.0006, respectively), and rs659964 was further associated with type 2 diabetes in the second American Indian sample (p=0.04). Combination of these two samples provided the strongest evidence for association (p=0.009 and 0.00007, for rs601663 and rs659964, respectively). Quantitative trait analyses identified nominal associations with both lower lipid oxidation rate and larger subcutaneous abdominal adipocyte size, which is consistent with the known physiology of ACAD10, and also identified associations with increased insulin resistance. CONCLUSIONS/INTERPRETATION:We propose that ACAD10 variation may increase type 2 diabetes susceptibility by impairing insulin sensitivity via abnormal lipid oxidation.

SUBMITTER: Bian L

PROVIDER: S-EPMC2947857 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Variants in ACAD10 are associated with type 2 diabetes, insulin resistance and lipid oxidation in Pima Indians.

Bian L L Hanson R L RL Muller Y L YL Ma L L Kobes S S Knowler W C WC Bogardus C C Baier L J LJ

Diabetologia 20100701 7

<h4>Aims/hypothesis</h4>A prior genome-wide association study in Pima Indians identified a variant within the ACAD10 gene that is associated with early-onset type 2 diabetes. Acylcoenzyme A dehydrogenase 10 (ACAD10) catalyses mitochondrial fatty acid beta-oxidation, which plays a pivotal role in developing insulin resistance and type 2 diabetes. Therefore, ACAD10 was analysed as a positional and biological candidate for type 2 diabetes.<h4>Methods</h4>Twenty-three SNPs were genotyped in 1,500 Pi ...[more]

PMID: 20390405

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Project description:ObjectivePrior genome-wide association and exon array expression studies both provided suggestive evidence that apoptosis signal regulating kinase 1 (ASK1) may influence in vivo insulin action in Pima Indians. Genetic variants in or near ASK1 were analyzed to assess the role of this gene in insulin action and type 2 diabetes.Research design and methodsGenotypic data from 31 variants were used to determine the linkage disequilibrium pattern across ASK1 in Pima Indians. Eight tag SNPs were initially genotyped in 3,501 full-heritage Pima Indians. Replication for association with diabetes was assessed in a second population-based sample of 3,723 Native Americans and the published DIAGRAM study. Quantitative traits were analyzed in 536 nondiabetic Native Americans, and ASK1 expression was examined in skeletal muscle of 153 nondiabetic Native Americans.ResultsThree tag SNPs were associated with type 2 diabetes (rs35898099, P = 0.003, odds ratio [95% CI] 1.27 [1.08-1.47]; rs1570056, P = 0.007, 1.19 [1.05-1.36]; rs7775356, P = 0.04, 1.14 [1.01-1.28]) in the full-heritage Pima Indians. The association with rs35898099 was replicated in a second sample of Native Americans (P = 0.04, 1.22 [1.01-1.47]), while that for rs1570056 was replicated in the DIAGRAM study of Caucasians (Z statistic based P = 0.026; fixed-effect model, 1.06 [1.00-1.12]). The diabetes risk allele for rs1570056 was associated with reduced insulin action as assessed by either HOMA-IR in 2,549 nondiabetic full-heritage Pima Indians (P = 0.027) or a hyperinsulinemic-euglycemic clamp among 536 nondiabetic Native Americans (P = 0.02). Real-time PCR identified a positive correlation between ASK1 expression in skeletal muscle biopsies and in vivo insulin action (P = 0.02, r = 0.23), and the risk allele for rs1570056 was associated with lower ASK1 expression (P = 0.003, r = -0.22).ConclusionsASK1 variants may increase susceptibility to type 2 diabetes by decreasing insulin sensitivity via reduced ASK1 expression.

Project description:The type 2 deiodinase gene (DIO2) encodes a deiodinase that converts the thyroid prohormone, thyroxine, to the biologically active triiodothyronine. Thyroid hormones regulate energy balance and may also influence glucose metabolism. Therefore, we hypothesized that variations in DIO2 could contribute to obesity or type 2 diabetes mellitus (T2DM) in Pima Indians.Sequencing of the DIO2 gene in DNA from 83 Pima Indians identified 12 single-nucleotide polymorphisms (SNPs). Several of these SNPs were in perfect genotypic concordance among the 83 samples that were sequenced, and all 12 could be divided into five linkage disequilibrium groups. One representative SNP from each group (Thr92Ala, rs225011, rs225015, rs6574549, and a rare 5' flanking SNP) was selected for further genotyping for association analyses. In this study, the five selected variants in DIO2, as described above, were genotyped in three groups of Pima Indians: (i) a case (n=150)/control (n=150) group for early-onset T2DM (onset age <25 years); (ii) a case (n=362)/control (n=127) group for obesity; (iii) a large (n=1,311, cases n=810/controls n=501) family-based group, of which 256 nondiabetic subjects had undergone detailed metabolic phenotyping.The Thr92Ala variant common in Pima Indians, rs225011, and rs225015 were modestly associated with early-onset T2DM (p=0.01-0.04) in the case-control study, but were not associated with obesity in the obesity case-control study, nor associated with T2DM (at any age) or body-mass index (BMI; as a quantitative trait) in the family-based analysis. Thr92Ala, rs225011, rs225015, and rs6574549 were also nominally associated with hepatic glucose output (p=0.02). rs6574549 was associated with fasting insulin (p=0.02), insulin action (p=0.04), and energy expenditure (p=0.02). None of these nominal associations remained statistically significant after corrections for multiple testing.We propose that variation in DIO2 may have a subtle role in altering metabolic processes that lead to early-onset T2DM, but this gene does not have a large impact on T2DM at older ages, nor does DIO2 influence BMI in the Pima Indian population.

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Variants in ACAD10 are associated with type 2 diabetes, insulin resistance and lipid oxidation in Pima Indians.

Publications

Variants in ACAD10 are associated with type 2 diabetes, insulin resistance and lipid oxidation in Pima Indians.

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